What can waning efficacy look or sound like?

Over time, repeated exposure to neurotoxins with complexing proteins can contribute to a decrease in treatment response.

Decreased Satisfaction1
Patients say the drug doesn't work as well as it used to
Increased Dosing1
Patients appear to require an increased dose in order to maintain efficacy or regain lost efficacy
Higher Frequency1
Patients are requesting shorter dosing intervals because they are experiencing decreased response
Loss of Patients
Patients feel less motivated to come back for reinjection or are lost to follow-up

Waning Efficacy and Neutralizing Antibodies

The FDA has issued guidance for the industry to conduct immunogenicity* evaluations of their products to appropriately assess the risk of NAb2:

A pair of boxing gloves, wraps, and a mouthguard. These are meant to symbolize the complexing proteins found in XEOMIN

Development of antibodies can limit product efficacy in patients treated with therapeutic protein products. NAb can block the efficacy of therapeutic protein products by specifically targeting domains critical for efficacy.”2

- FDA Guidance on Immunogenicity Assessment for Therapeutic Protein Products

Signs of Waning Efficacy with Chronic, Long-term Exposure to Complexing Proteins in Neurotoxin Formulations

NAb formation does not occur in all patients, but because of its increasing likelihood with long-term neurotoxin use, it should be considered when starting or adjusting therapy.1

A chart showing the cyclical nature of waning efficacy in neurotoxin formulations with complexing proteins

COMPLEXING PROTEINS MAY CONTRIBUTE TO NAb FORMATION

Up to 83% of the total protein mass in neurotoxin formulations containing complexing proteins has no therapeutic activity and may potentially increase the risk of waning efficacy over time.1,3-5
An illustration of complexing proteins: hemagglutinin, non-toxin, non-hemagglutinin, and core neurotoxin
Learn About Xeomin

The FDA defines immunogenicity as “the propensity of a therapeutic protein product to generate immune responses to itself and to related proteins or to induce immunologically related adverse clinical events.”2

The direct impact of the non-therapeutic proteins on long-term safety or efficacy continues to be evaluated. Information about the unique XEOMIN manufacturing process and the properties of incobotulinumtoxinA is not intended to imply superiority over other botulinum toxin type A products.

Neutralization is possible with all neurotoxins with or without complexing proteins.

FDA, US Food and Drug Administration; NAb, neutralizing antibodies.

An illustration of the XEOMIN molecule without complexing proteins

XEOMIN Contains Only the Active Neurotoxin1,3,4

XEOMIN is a neurotoxin specifically designed with just the therapeutic component, making it up to 6 times lower in molecular weight than formulations with complexing proteins.1,3,4

The unique molecular profile of XEOMIN is developed using proprietary XTRACT Technology—a state-of-the-art manufacturing process that removes complexing proteins to minimize waning efficacy as a result of immunogenicity.6

An illustration of the XEOMIN molecule without complexing proteins

In retrospective studies, NAb were more likely to develop over time after treatment with a neurotoxin formulation with a higher molecular weight1,3,4

XTRACT Technology ®

Watch XTRACT Technology in Action

PATIENTS DID NOT DEVELOP NAb-RELATED CLINICAL RESISTANCE TO XEOMIN

XEOMIN Pivotal Studies

In more than 2600 patients treated with XEOMIN in pivotal clinical trials, there were no reports of waning efficacy due to NAb formation1,7

1490 adult patients were treated with XEOMIN. 1159 pediatric patients were treated with XEOMIN. 0 patients with clinical resistance to XEOMIN due to NAb

All patients who developed NAb were previously treated with Botox® and/or Dysport®, and out of the 0.6% of patients (9 adult, 4 pediatric) where NAb were present, none developed clinical resistance1

In a separate, independent, monocenter, retrospective cohort study5

49 patients treated exclusively with XEOMIN. 0 reports of waning efficacy due to Nab. Average length of treatment 8.4 years

WATCH IMMUNOLOGIST DR WARNER CARR DISCUSS THE IMPACT OF NAb ON TREATMENT RESPONSE

See the Science Behind XEOMIN: Mechanism of Action

Manufacturers use a selected strain of Clostridium botulinum, bred biologically in optimal conditions, to produce therapeutic botulinum toxin products.7

XEOMIN is a botulinum toxin type A that blocks transmission at the neuromuscular junction by inhibiting the release of ACh from peripheral cholinergic nerve endings.7

In both muscle and glands, impulse transmission is reestablished by the formation of new nerve ends.7

See the head-to-head studies

The direct impact of the non-therapeutic proteins on long-term safety or efficacy continues to be evaluated. Information about the unique XEOMIN manufacturing process and the properties of incobotulinumtoxinA is not intended to imply superiority over other botulinum toxin type A products.

Neutralization is possible with all neurotoxins, including XEOMIN.

The potency Units of XEOMIN are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.

NAb, neutralizing antibodies; ACh, acetylcholine.

Consistently Proven in Head-to-Head Studies

Noninferiority: XEOMIN vs active comparator (Botox®)

XEOMIN and Botox (onabotulinumtoxinA) were proven safe and effective in treating the symptoms of cervical dystonia as measured by the TWSTRS score at Week 4, and blepharospasm as measured by the JRS sum score at Week 3.8,9

The corner rope of a boxing ring. This is meant to symbolize the noninferiority between XEOMIN and Botox
Efficacy: Adult Cervical Dystonia XEOMIN vs Botox8

Similar improvement from baseline in TWSTRS severity score

A graph showing the efficacy of XEOMIN vs Botox in adults with cervical dystonia See the Full Study Details
Efficacy: Adult Blepharospasm XEOMIN vs Botox9

Similar improvement from baseline in JRS sum score

A graph showing the efficacy of XEOMIN vs Botox in adults with blepharospasm See the Full Study Details
Safety results were comparable between products, with no new or unexpected safety signals

XEOMIN Has Demonstrated Similar Duration of Effect to Botox

Duration of effect: XEOMIN vs active comparator (Botox)

In noninferiority studies comparing XEOMIN with Botox in adult patients with cervical dystonia or blepharospasm, days to onset of effect and days of duration of effect were similar for the 2 treatments.8,9

The corner rope of a boxing ring. This is meant to symbolize the duration of effect for XEOMIN when compared to Botox
Adult Cervical Dystonia – Onset and Duration After Treatment8
Adult Cervical Dystonia – Onset and Duration After Treatment8
A chart showing the onset and duration of effects from XEOMIN on patients with adult cervical dystonia when compared to Botox See the Full Study Details
Adult Blepharospasm – Onset and Duration After Treatment9
A chart showing the onset and duration of effects from XEOMIN on patients with adult blepharospasm when compared to Botox See the Full Study Details

Safety results were comparable between products, with no new or unexpected safety signals

See the Indications

§ Patient-reported outcome: onset and waning of effect were subjectively estimated by the patient at control and end-of-study visits.

‡ Investigator assessment of duration of effect was calculated based on the time between the initial injection and the end-of-study visit (return to 80% of baseline TWSTRS severity score).

|| Duration of effect was calculated based on the time between the initial injection and the end-of-study visit (when the subject and the investigator agreed that a new injection was needed).

The potency Units of XEOMIN are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.

TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale; JRS, Jankovic Rating Scale.

References

  1. Carr WW, Jain N, Sublett JW. Immunogenicity of botulinum toxin formulations: potential therapeutic implications.  Adv Ther. 2021;38(10):5046-5064.
  2. US Food and Drug Administration: Immunogenicity Testing of Therapeutic Protein Products – Developing and Validating Assays for Anti-Drug Antibody Detection. Accessed January 20,2023. https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/immunogenicity-testing-therapeutic-protein-products-developing-and-validating-assays-anti-drug
  3. Frevert J. Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs R D. 2010;10(2):67-73.
  4. Frevert J. Pharmaceutical, biological, and clinical properties of botulinum neurotoxin type A products. Drugs R D. 2015;15(1):1-9.
  5. Walter U, Mühlenhoff C, Benecke R, et al. Frequency and risk factors of antibody-induced secondary failure of botulinum toxin therapy. Neurology. 2020;94(20):e2109-e2120.
  6. Kerscher M, Wanitphakdeedecha R, Trindade de Almeida A, Maas C, Frevert J. IncobotulinumtoxinA: a highly purified and precisely manufactured botulinum neurotoxin type A. J Drugs Dermatol. 2019;18(1):52-57.
  7. XEOMIN® [Package insert]. Raleigh, NC: Merz Pharmaceuticals, LLC; 2023.
  8. Benecke R, Jost WH, Kaňovský P, Ruzicka E, Comes G, Grafe S. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology. 2005;64(11):1949-1951.
  9. Roggenkämper P, Jost WH, Bihari K, Comes G, Grafe S; NT 201 Blepharospasm Study Team. Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm.  J Neural Transm (Vienna). 2006;113(3):303-312.
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IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
WARNING:
DISTANT SPREAD OF TOXIN EFFECT

See full prescribing information for complete BOXED WARNING.

The effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms.

INDICATIONS

XEOMIN® (incobotulinumtoxinA) for injection is indicated for the treatment of:

  • Chronic sialorrhea in patients 2 years of age and older
  • Upper limb spasticity in adults
  • Upper limb spasticity in pediatric patients 2 years of age and older, excluding spasticity caused by cerebral palsy
  • Cervical dystonia in adults
  • Blepharospasm in adults
CONTRAINDICATIONS
  • Known hypersensitivity to any botulinum toxin product or to any of the components in the formulation.
  • Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.
WARNINGS AND PRECAUTIONS
  • The potency units of XEOMIN are specific to the preparation and assay method used and are not interchangeable with other preparations of botulinum toxin products. Therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products.
  • Serious hypersensitivity reactions have been reported with botulinum toxin products (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea). If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately. The use of XEOMIN in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction.
  • Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. When distant effects occur, additional respiratory muscles may be involved. Patients may require immediate medical attention should they develop problems with swallowing, speech, or respiratory disorders. Dysphagia may persist for several months, which may require use of a feeding tube. Aspiration may result from severe dysphagia [See BOXED WARNING].
  • Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.
  • Caution should be taken when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy.
  • Cervical Dystonia: Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post- marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles are at greater risk of dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.
  • Blepharospasm: Injection of XEOMIN into the orbicularis oculi muscle may lead to reduced blinking and corneal exposure with possible ulceration or perforation. To decrease the risk for ectropion, XEOMIN should not be injected into the medial lower eyelid area.
  • XEOMIN contains human serum albumin. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been reported for albumin.
ADVERSE REACTIONS

The most commonly observed adverse reactions at rates specified below and greater than placebo are:

  • Chronic Sialorrhea:
    • in adults (≥4% of patients): tooth extraction, dry mouth, diarrhea, and hypertension.
    • in pediatric patients (≥1% of patients): bronchitis, headache, and nausea/vomiting.
  • Upper Limb Spasticity
    • in adults (≥2% of patients): seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection.
    • in pediatric patients (≥3% of patients): nasopharyngitis and bronchitis.
  • Cervical Dystonia in adults (≥5% of patients): dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.
  • Blepharospasm in adults (≥10% of patients): eyelid ptosis, dry eye, visual impairment, and dry mouth.
DRUG INTERACTIONS

Co-administration of XEOMIN and aminoglycoside or other agents interfering with neuromuscular transmission, (e.g., muscle relaxants), should only be performed with caution as these agents may potentiate the effect of the toxin.

Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

USE IN PREGNANCY

There are no adequate data on the developmental risk associated with the use of XEOMIN in pregnant women. XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

PEDIATRIC USE

Safety and effectiveness of XEOMIN in patients less than 18 years of age have not been established for lower limb spasticity, cervical dystonia, or blepharospasm. Safety and effectiveness have been established in pediatric patients 2 to 17 years of age in patients with chronic sialorrhea and upper limb spasticity. A pediatric assessment for XEOMIN in upper limb spasticity demonstrates that XEOMIN is safe and effective in another pediatric population. However, XEOMIN is not approved for such patient population due to marketing exclusivity for another botulinum toxin.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
WARNING:
DISTANT SPREAD OF TOXIN EFFECT

See full prescribing information for complete BOXED WARNING.

The effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms.

INDICATIONS

XEOMIN® (incobotulinumtoxinA) for injection is indicated for the treatment of:

  • Chronic sialorrhea in patients 2 years of age and older
  • Upper limb spasticity in adults
  • Upper limb spasticity in pediatric patients 2 years of age and older, excluding spasticity caused by cerebral palsy
  • Cervical dystonia in adults
  • Blepharospasm in adults
CONTRAINDICATIONS
  • Known hypersensitivity to any botulinum toxin product or to any of the components in the formulation.
  • Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.
WARNINGS AND PRECAUTIONS
  • The potency units of XEOMIN are specific to the preparation and assay method used and are not interchangeable with other preparations of botulinum toxin products. Therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products.
  • Serious hypersensitivity reactions have been reported with botulinum toxin products (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea). If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately. The use of XEOMIN in patients with a known hypersensitivity to any botulinum neurotoxin or to any of the excipients (human albumin, sucrose), could lead to a life-threatening allergic reaction.
  • Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. When distant effects occur, additional respiratory muscles may be involved. Patients may require immediate medical attention should they develop problems with swallowing, speech, or respiratory disorders. Dysphagia may persist for several months, which may require use of a feeding tube. Aspiration may result from severe dysphagia [See BOXED WARNING].
  • Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.
  • Caution should be taken when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy.
  • Cervical Dystonia: Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post- marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles are at greater risk of dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.
  • Blepharospasm: Injection of XEOMIN into the orbicularis oculi muscle may lead to reduced blinking and corneal exposure with possible ulceration or perforation. To decrease the risk for ectropion, XEOMIN should not be injected into the medial lower eyelid area.
  • XEOMIN contains human serum albumin. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been reported for albumin.
ADVERSE REACTIONS

The most commonly observed adverse reactions at rates specified below and greater than placebo are:

  • Chronic Sialorrhea:
    • in adults (≥4% of patients): tooth extraction, dry mouth, diarrhea, and hypertension.
    • in pediatric patients (≥1% of patients): bronchitis, headache, and nausea/vomiting.
  • Upper Limb Spasticity
    • in adults (≥2% of patients): seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection.
    • in pediatric patients (≥3% of patients): nasopharyngitis and bronchitis.
  • Cervical Dystonia in adults (≥5% of patients): dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.
  • Blepharospasm in adults (≥10% of patients): eyelid ptosis, dry eye, visual impairment, and dry mouth.
DRUG INTERACTIONS

Co-administration of XEOMIN and aminoglycoside or other agents interfering with neuromuscular transmission, (e.g., muscle relaxants), should only be performed with caution as these agents may potentiate the effect of the toxin.

Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

USE IN PREGNANCY

There are no adequate data on the developmental risk associated with the use of XEOMIN in pregnant women. XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

PEDIATRIC USE

Safety and effectiveness of XEOMIN in patients less than 18 years of age have not been established for lower limb spasticity, cervical dystonia, or blepharospasm. Safety and effectiveness have been established in pediatric patients 2 to 17 years of age in patients with chronic sialorrhea and upper limb spasticity. A pediatric assessment for XEOMIN in upper limb spasticity demonstrates that XEOMIN is safe and effective in another pediatric population. However, XEOMIN is not approved for such patient population due to marketing exclusivity for another botulinum toxin.